Stereoselective Conjugate Additions of Hydrazines, Oximes, and Hydroxylamines to α,β-Unsaturated Imides

CHAPTER 5

Stereoselective Conjugate Additions of Hydrazines, Oximes, and Hydroxylamines to α,β-Unsaturated Imides Anna C. Renner and Mukund P. Sibi Department of Chemistry and Biochemistry, North Dakota State University, Fargo, ND, United States

5.1 INTRODUCTION The development of enantioselective transformations remains a major objective in synthetic organic chemistry; the ability to selectively obtain one enantiomer of a product is key to the efficient preparation of many pharmaceuticals and natural products. Of particular note here is the use of amide-based auxiliaries/templates, such as oxazolidinones, for enantioselective conjugate additions to α,β-unsaturated carbonyl compounds. Installment of the auxiliary yields an imide that can coordinate to Lewis acids via its carbonyl oxygens, not only increasing the electrophilicity of the β carbon but also potentially restricting rotation around the amide bonds and thereby enforcing an s-cis conformation of the alkenoyl group to avoid steric interactions with the auxiliary. The chirality of the product can be derived from the use of a chiral reagent, a chiral auxiliary/template, a chiral ligand for the Lewis acid, or preexisting chirality within the substrate. While enantioselective reactions have been developed for conjugate additions of many different nucleophiles to carbonyl compounds, this chapter focuses on conjugate additions to α,β-unsaturated imides by nucleophiles containing N
N and N
O bonds: hydrazines, oximes, and hydroxylamines. These compounds are exceptionally nucleophilic due to the α-effect: the presence of an unshared electron pair on the N or O next to the more nucleophilic heteroatom imparts enhanced nucleophilicity. The resulting heteroatom-containing products themselves are potentially useful for applications in medicinal chemistry or natural products Imides DOI: https://doi.org/10.1016/B978-0-12-815675-9.00005-9

© 2019 Elsevier Inc. All rights reserved.

139

140

Imides

synthesis, and the products’ heteroatom
heteroatom bonds may alternatively be reductively cleaved to afford additional, distinct structures such as β-amino acids and β-hydroxy imides. The past 25 years have seen numerous advances in the area of enantioselective conjugate additions of N
N and N
O nucleophiles to α,β-unsaturated imides, and in this chapter, we have sought to comprehensively review not only the development of methods enabling such transformations but also their application for the efficient synthesis of target structures. When relevant, asymmetric conjugate additions to other enoates are included. The following discussion of the literature is divided into sections for each type of nucleophile—hydrazines, oximes, O-substituted hydroxylamines, and N-substituted hydroxylamines—and is further organized to highlight strategies for stereoinduction and chronological trends. We conclude the chapter by summarizing the studies reported to date and the current state of the science with the hope that this review will inform future innovations in the development or application of asymmetric synthesis.

5.2 HYDRAZINES Stereoselective conjugate addition of hydrazines to α,β-unsaturated imides is underexplored. An early report of stereoselective hydrazine addition, albeit to α,β-unsaturated esters, was by Enders et al.,1 who employed as nucleophiles the enantiomeric hydrazines TMS-SAMP and TMS-RAMP (Scheme 5.1). TMS-SAMP and TMS-RAMP were readily prepared from (S)- and (R)-1-amino-2-(methoxymethyl)pyrrolidine (SAMP and RAMP, O R1

TMS-SAMP (1.3 equiv.) OR2

n-BuLi, THF, –78°C

OMe SiMe3 N O N R1

1 R1 = Alkyl R2 = Me, t-Bu

OR2 2

OMe N HN

SiMe3

OMe SiO2, Ethyl acetate

N NH O Quant. 32%–67% (two steps) R1 OR2 3 de = 93%–98% Raney Ni, H2 H2O, 60–75°C 50%–86%

TMS-SAMP NH2 O R1

OH 4 ee = 90%–98%

Scheme 5.1 Asymmetric conjugate additions of chiral hydrazines.1

Stereoselective Conjugate

141

known for their use as chiral auxiliaries), respectively. After deprotonation using n-butyllithium, TMS-SAMP reacted with β-alkyl-substituted alkyl esters 1 to afford conjugate addition products 2, although methyl esters also underwent 1,2-addition. Desilylation of the crude products using silica gel in ethyl acetate gave products 3 in low to moderate yields (32%
67% over both steps) and 93%
98% de, and subsequent hydrogenolysis over Raney nickel yielded the corresponding β-amino acids 4 in 50%
86% yield and 90%
98% ee. The same reaction sequence with methyl crotonate as substrate and TMS-RAMP as nucleophile afforded (R)-3-aminobutanoic acid in similar yield and selectivity. Enders and Wiedemann later employed asymmetric conjugate addition of TMS-SAMP to construct five-, six-, and seven-membered carbocyclic and heterocyclic β-amino acids and esters starting with ω-halidesubstituted α,β-unsaturated esters (Scheme 5.2, see conversion of 5
7 and 8
10).2 With different halide-substituted esters and reaction conditions, each conjugate addition product either directly formed a carbocycle by intramolecular alkylation of its enolate or was converted to an N-heterocycle in a one-pot procedure effecting desilylation followed by intramolecular N-alkylation. The resulting desilylated β-hydrazino esters were obtained in low to moderate yields but excellent diastereoselectivities and were readily converted to chiral β-amino esters and acids. To account for the products’ absolute stereochemistry, the authors proposed model 11 in which the bulky silyl group of TMS-SAMP would hinder a re-face approach of the nucleophile, thereby favoring nucleophilic attack from the si face of the enoate. Another example of asymmetric hydrazine addition under basic conditions was reported by Seki and coworkers, who used the (1S)(
)-2,10-camphorsultam-derived substrate 12 as the chiral source in conjugate additions of cycloaliphatic hydrazines to cinnamates (Scheme 5.3).3 Bicyclic products 15 and 16 that would result from conjugate addition and subsequent cyclization had previously been used in syntheses of the spermidine and spermine alkaloids (S)-celacinnine and (S,S)-homaline. To enantioselectively prepare 15, the authors first conducted the reaction in tetrahydrofuran with 5 equiv. of piperidazine 13 and varying amounts of n-butyllithium. Although the reaction gave 44% ee in the absence of n-butyllithium, the enantioselectivity increased with the amount of base, reaching 66% ee when 5 equiv. of n-butyllithium was used. In further experiments, diethyl ether gave the highest enantioselectivity (86% and 77% ee for 15 and 16, respectively) when evaluated in a screen of several

142

Imides

1. TMS-SAMP n-BuLi THF, –78°C

O X

OMe N

Ot-Bu 2. HMPA, –78°C (n = 3, 4) 3. NaHCO3, H2O

n 5

X

n

NH2

SiMe3

CO2H

CO2t-Bu

de = 96%–98% ee ≥ 98%

de ≥ 96% 1. TMS-SAMP n-BuLi THF, –78°C Ot-Bu

n–2

7

n–2

6

X = Br, I n = 2, 3, 4

O

N

OMe

2. NaHCO3, H2O

8 X = Cl, Br n = 2, 3, 4

N N

Me3Si X 9

H N

CO2t-Bu

CO2t-Bu n–2

10

n–2

ee = 97% (n = 2)

de ≥ 96%

Me N

Me Si

re-face

Me

N

O Li

Me R O

11

RO Me Me Si Me

si-face

N N Li O Me

Scheme 5.2 Synthesis of carbocyclic and heterocyclic β-amino acids using conjugate addition of a chiral hydrazine.2

O O S O2

NH NH

+

N

Ph 12

13 (5 equiv.)

Li

n-BuLi (5 equiv.) Et2O, 0°C, 24 h; rt, 24 h

N

NH

O N N

Ph

14 (5 equiv.)

si-face attack

N

18

NH NH

15

N N

or Ph

+ S 17 O2

16

NH

O

Conjugate addition

O S O O

or

O S O O 19

(S)

Cyclization

N N

N Li

N

N

Ph 20 (up to 86% ee)

Scheme 5.3 Stereoselective conjugate additions of cyclic hydrazines using camphorsultam auxiliary.3

143

Stereoselective Conjugate

ethereal solvents as well as toluene. The chiral auxiliary 17 could be recovered. Other cinnamates with electron-withdrawing and electrondonating groups gave low to excellent yields and 46%
64% ee in room temperature reactions with pyrazolidine 14 in diethyl ether/tetrahydrofuran without n-butyllithium. However, under the optimal conditions (5 equiv. of n-butyllithium in diethyl ether at 0°C), p-methoxy and p-nitro cinnamates were converted to the corresponding products with significantly higher yield from the p-methoxy cinnamate (88% compared with 12% previously obtained) and higher (86%) ee from the p-nitro cinnamate. To explain the observed stereoselectivity, the authors proposed a model in which the steric influence of the auxiliary would favor si-face attack of the hydrazine to the cinnamate (see 18
20). In 2007 Sibi and Soeta reported chiral Lewis acid
catalyzed conjugate additions of monoalkyl-substituted hydrazines 22 to achiral 21 to yield chiral pyrazolidinones (Scheme 5.4).4 In these reactions, the formation of a single optically pure product required not only enantioselectivity but also chemoselectivity: either nitrogen of the alkylhydrazine could attack the enoate’s β carbon, potentially resulting in different stereoisomers and constitutional isomers. Several Lewis acids and crotonates (21, R1 5 Me) with different templates were screened in the reaction with benzylhydrazine using ligand 26 at room temperature, 230°C, and 250°C. The use of magnesium perchlorate and the benzimide template 25e at 250°C furnished the highest enantioselectivity of the major product, 23, formed via attack of the more-nucleophilic alkyl-substituted nitrogen. In an evaluation of enoate and hydroxylamine scope, good to excellent yields, high

O R2

+ Z

R1

N H

NH2

· 2HCl 21 R1 = Alkyl, Bn, CH2OBn, Ph, CO2t-Bu

Lewis acid/ligand 26 (30 mol%) Et3N, MS 4Å CH2Cl2

22 R2 = Bn, Alkyl O

Z= X

N

25a X = O 25b X = CH2

R1

N H

25d R = t-Bu 25e R = Ph

N R2 N H 24 X

Ph

X

O HN

N 26

R 25c

+

Mg O

O

N

N

R1

O

N H N R2 23

O N

O

O

H2N

N

O

N NH R2

R1

O 27

Scheme 5.4 Chemoselective and enantioselective conjugate additions of hydrazines to β-substituted acrylimides.4

144

Imides

isomer ratios (23/24 . 95:5), and good to excellent enantioselectivities were generally obtained, although lower yields and/or selectivities resulted in reactions of benzylhydrazine with enoates bearing template 25e and phenyl, isopropyl, and ester β substituents. Reactions of methylhydrazine and isopropylhydrazine with two of the substrates (21, R1 5 Me, CH2OBn) provided high enantioselectivities (up to 99% ee); the corresponding reactions of cyclohexylhydrazine afforded moderate to good ee. The authors noted that the major product’s absolute stereochemistry could be explained by conjugate addition to the substrate in its s-cis rotamer in an octahedral complex, 27.

5.3 OXIMES In conjugate additions, either heteroatom of an oxime can potentially react as the nucleophile: O-reactivity leads to the formation of oxime ethers while N-reactivity results in nitrone products. In 2002 Nakama and coworkers reported an enantioselective example of the latter reaction catalyzed by the aqua complex of Zn(ClO4)2  6H2O and the R,R-DBFOX/ Ph ligand 33 (Scheme 5.5).5 Noting the potential of oximes to strongly bind and possibly deactivate a catalytic metal complex, the authors surmised that aqua complexes of 33 with metal salts, which had previously demonstrated robust activity in the presence of strongly binding nucleophiles, might successfully catalyze the reaction. Indeed, complexes of 33 with various metal salts promoted the room temperature conjugate addition of benzaldoxime (28, R 5 Ph) to oxazolidinone crotonate 29, but the reactions gave insignificant enantioselectivity. The highest yield of the R O

O RCH = NOH +

28 R = Ph, 2-furyl, 2-thienyl, (E)-PhCH = CH-

Zn(ClO4)2·6H2O/33 (10 mol%)

N

X

N

O

O

O N

CH2Cl2

29 X = O 30 X = NPh

31 X = O 32 X = NPh O O

N Ph

33

N

O

Ph

Scheme 5.5 Enantioselective conjugate additions of oximes to yield nitrones.5

X

145

Stereoselective Conjugate

nitrones 31 or 32 resulted from the use of Zn(ClO4)2  6H2O when the reactants were slowly added simultaneously to a dichloromethane solution of the catalyst. Under these conditions, more-reactive 2-furyl, 2-thienyl, and styryl aldoximes formed the corresponding nitrone products in good yields but very poor enantioselectivity. Replacement of the oxazolidinone auxiliary with the more strongly coordinating imidazolidinone auxiliary 30 allowed for improved reactivity and enantioselectivity in the reactions of all four oximes, although enantioselectivities were generally still low. As the most successful example, the reaction of 2-furyl 28 at 0°C gave 64% ee; further lowering the temperature to 240°C for this reaction drastically decreased yield and only marginally increased enantioselectivity. Various other Lewis acid catalysts were evaluated in the reaction but afforded no improvements in enantioselectivity. Vanderwal and Jacobsen exploited the reactivity of oximes (35) as O-nucleophiles as a means to effect enantioselective formal hydration enabling the synthesis of chiral β-hydroxy carboxylic acid derivatives 38 (Scheme 5.6).6 Through screening a variety of oximes, (salen)aluminum

O R

OH

O N H

Ph

34

N

+

OH N

(R,R)-39b (5 mol%) Cyclohexane, 23°C, 48 h

OH

O

R

35

36

N H

Ph

H2, Pd(OH)2/C AcOH, EtOH, 23°C

R = Me, Et, i-Pr, O i-Pr O

OH O R

MOMO

37

O N H

Ph

Er(OTf)3 (cat.) EtOH, 4°C

TBSO MOMO (Salen)Al-X:

Me Me

O

O

O O

OH O H N

Me

H

R

N

t-Bu

O

O

OEt 38

Al t-Bu

X

MOMO

Me

t-Bu t-Bu 39a X = Me 39b X = O-Al(salen)

Scheme 5.6 Formal hydration strategy using enantioselective conjugate addition of salicylaldoxime.6

146

Imides

catalysts 39 (which had previously promoted enantioselective reactions of weakly acidic nucleophiles), and solvents, they identified optimal conditions—reaction with salicylaldoxime catalyzed by 39b in cyclohexane—that subsequently converted α,β-unsaturated benzimides 34 to the corresponding adducts 36 in excellent conversions and 97%
98% ee. Hydrogenolysis of the oxime adducts afforded the corresponding β-hydroxy imides 37 in 81%
93% isolated yields over the two steps. To demonstrate the potential utility of the conjugate addition in polyketide natural products synthesis, the authors used the (R,R) and (S,S) enantiomers of the catalyst to convert MOM- and acetonide-protected chiral imides to the corresponding formal hydration products in 70%
89% yields and 47:1 to .99:1 ratios of diastereomers. Finally, Er(OTf)3catalyzed ethanolysis of selected β-hydroxy imides gave the corresponding ethyl esters in 89%
98% yield.

5.4 O-SUBSTITUTED HYDROXYLAMINES Conjugate addition of O-substituted hydroxylamines to α,β-unsaturated imides has been an attractive approach notably for the synthesis of β-amino acid precursors. Stereoselective reactions of this type typically have been performed using α,β-unsaturated imides with either one β substituent or one α substituent. Whereas the reactions of β-substituted acrylimides require stereocontrol over the approach of the nucleophile, those of α-substituted acrylimides involve stereoselective protonation of the enolate resulting from conjugate addition. For the latter, asymmetric induction has been achieved with the use of chiral oxazolidinone auxiliaries, and the conjugate addition products have served as important intermediates in syntheses of pharmaceutically relevant compounds, often in industry settings. For the former, a greater number and variety of strategies have been developed and applied to achieve stereocontrol at the β carbon. As detailed in Section 5.4.1, methods have included the use of a chiral auxiliary with an achiral Lewis acid or an achiral auxiliary with a chiral Lewis acid; additionally, one report has described achiral Lewis acid
catalyzed conjugate addition to a chiral substrate with an achiral auxiliary, resulting in substrate-controlled diastereoselectivity.

147

Stereoselective Conjugate

5.4.1 Conjugate Addition to β-Substituted Acrylimides 5.4.1.1 Use of Chiral Substrates In a 2002 paper, Cardillo et al. described diastereoselective conjugate additions of O-benzylhydroxylamine to trans- and cis-enoates 40 and 41 derived from D-glyceraldehyde and bearing an oxazolidinone auxiliary (Scheme 5.7).7 The authors screened several Lewis acids in dichloromethane and/or THF at 210°C (or 260°C for AlMe2Cl). In the reaction of the trans enoate, the use of Sc(OTf)3 and MgBr2  Et2O afforded no diastereoselectivity while the use of Yb(OTf)3, Bu2BOTf, CeCl3  7H2O, and AlMe2Cl gave moderate diastereoselectivities. Interestingly, Yb(OTf)3 and Bu2BOTf afforded diastereoselectivities opposite to those obtained with CeCl3  7H2O and AlMe2Cl. The authors obtained better results in reactions with the cis enoate. Upon screening several Lewis acids, they achieved good to excellent yields and diastereoselectivities with CeCl3  7H2O, Cu(OTf)2, and MgBr2  Et2O, with the best results (yield . 98% and 42/43 . 99:1) obtained using MgBr2  Et2O. Further reactions promoted by different Lewis acids allowed product 42 to be selectively converted to diverse structures: ester 44, trans-aziridine 45, dihydro uracil 46, and lactone 47. BnO

1) Lewis acid CH2Cl2 and/or THF –10°C

O N

O

O

O O

O N

O O

O

42

O

+

2) BnONH2

BnO

40

NH

NH

BnO OMe

NH

BnO

O

O

O 47

O

O BnO N O

O 45

NH

HO

O

H O N O

O

O

O 42

N

41

N

44

O

O

43

O

O

O

N O

O

O

O

2) BnONH2

O

O

NH2 O

1) Lewis acid CH2Cl2 and/or THF –10°C

O

N

OH

N O

O O

46

Scheme 5.7 Lewis acid
catalyzed transformations of D-glyceraldehyde-derived imides.7

148

Imides

5.4.1.2 Use of Chiral Auxiliaries In 1993 Amoroso, Cardillo, and coworkers reported Lewis acid
promoted diastereoselective conjugate additions of O-benzylhydroxylamine to (4S,5R)-3-alkenylimidazolidin-2-ones 48 (Scheme 5.8).8 Several Lewis acids were tested and gave varying yields and diastereoselectivities. Higher diastereoselectivities and good yields were achieved with the use of TiCl4 and AlMe2Cl (up to 11:83 dr for 49/50 in AlMe2Cl-promoted reactions). Interestingly, these two Lewis acids gave opposite diastereoselectivities. To explain the diastereoselectivity obtained with AlMe2Cl, the authors invoked the formation of chelate 51 and preferential attack of O-benzylhydroxylamine at the s-cis conformation’s less-hindered Cβ-re face. To rationalize the opposite diastereoselectivity obtained with TiCl4, they suggested that the Ti
O
C bond lengths and angles in a chelate complex, if similar to those reported for TiCl4
ethyl O-acryloyllactate,9 would favor conformation 52 over 53 with Ti under the planes of the carbonyls, away from the bulky phenyl substituent, forcing the alkenoyl group above the carbonyl planes and thereby promoting si-face attack. Finally, the authors demonstrated the application of their methodology for the enantioselective synthesis of a β-amino acid, (1)-(S)-3-butanoic acid, which involved reductive cleavage of the N
O bond and hydrolysis to remove the auxiliary following the conjugate addition step. In 2000 Cardillo, Gentilucci, and coworkers described a similar but MgBr2-promoted conjugate addition of O-benzylhydroxylamine as an early step in their synthesis of a dipeptide fragment in the antibiotic Lysobactin (Scheme 5.9).10 In the presence of MgBr2  Et2O, a cinnamoyl O Me N

O N

Me

R

Ph

O

1) M(L)n dry CH2Cl2

Me N

2) BnONH2 dry CH2Cl2

Me

48

O

O

NHOBn

N

Me N +

R

Ph

Me

49

O

NHOBn

N

R

Ph 50

R = CH3, n-C3H7

Cl

Cl

Cl Ti H N N

O O

Al

AlCl2–

H

H si

re

N N

51

O Cl 52 Favored

O Ti

N

Cl H Cl

N O O

H H

Cl re

Cl 53 Disfavored

Scheme 5.8 Lewis acid
promoted conjugate additions and models explaining diastereoselectivity.8

149

Stereoselective Conjugate

O Me N

O N

Me

Ph

Ph

O

NH2OBn MgBr2•Et2O

Me N

CH2Cl2 90%

Me

O

O

NHOBn

N

Ph

+

Ph

54

NHOBn

O

Me N

N

Me

Ph

55

56 O

O O Me N

O N

Me

O

NHOBn Ph

AlMe2Cl

Me N

TEA, CH2Cl2 60%

Ph

O N

Me

55

H N

O

Ph

Ph

CH2Cl2 65%

O

HN Ph 59

Me N

O

O Me

Ph N

Me

1) LiOOH, THF/H2O MeO 2) CH2N2 75%

HN 60 O

Ph FMOC N H 58

TEA, DMAP, CH2Cl2 75%

Ph NHFMOC Me

O N

NH Me FMOC

OH

N

Me

Me

Cl

57

BF3•Et2O Me N H2O, piperidine

(80:20 dr)

Ph

O

Me Me

OH Ph NHFMOC Me Me

Scheme 5.9 Use of MgBr2-promoted conjugate addition for the synthesis of a dipeptide fragment.10

derivative of the chiral template (4S,5R)-1,5-dimethyl-4-phenylimidazolidin-2-one 54 underwent conjugate addition by O-benzylhydroxylamine to its less-hindered face, affording a 90% yield of the readily separated diastereomers 55 and 56 in 80:20 dr. Treatment of each product with AlMe2Cl and triethylamine in dichloromethane gave the corresponding trans aziridines 57, which were subsequently coupled to N-protected acid chlorides derived from leucine. Each aziridine underwent regioselective and stereoselective ring expansion to the corresponding oxazoline. Conditions for oxazoline ring opening were investigated with the (40 R,50 S) oxazoline and later applied to its diastereomer (40 S,50 R)-58 to yield the ring-opened compound 59. Removal of the chiral auxiliary followed by methylation of the free acid led to the final dipeptide fragment 60 present in Lysobactin. In a 2001 paper,11 Hanessian et al. also described diastereoselective conjugate additions of O-benzylhydroxylamine to 61 en route to aziridines, which they desired as precursors to aziridine-based constrained analogs of their recently reported acyclic matrix metalloproteinase inhibitors. They screened several Lewis acids and chiral auxiliaries, including AlMe2Cl, TiCl4, and the auxiliary used in Cardillo et al.’s 1993 paper (see 54). Although they obtained generally good yields, they were unsatisfied with the diastereoselectivities; as one of the best results, a 73:27 ratio of inseparable diastereomers 62/63 (R 5 i-Pr) was obtained with Cardillo et al.’s methods using AlMe2Cl. Drawing from Cardillo et al.’s

150

Imides

stereochemical models (Scheme 5.8) and considering the use of planar Bu2BOTf complexes in auxiliary-based asymmetric aldol reactions, the authors tested Bu2BOTf as a potentially more-effective Lewis acid in the conjugate addition reaction. Bu2BOTf-promoted reactions afforded 62/63 in 88%
93% yield and $ 95:5 dr (Scheme 5.10). Continuing their work toward the stereoselective synthesis of β-hydroxy-α-amino acids, Cardillo et al. described methodology for the preparation of oxazolines 69 as precursors of syn-hydroxyleucine, an amino acid in the antibiotic Lysobactin (Scheme 5.11).12 As in Scheme 5.9, their strategy was based on diastereoselective conjugate addition of O-benzylhydroxylamine to 64 followed by aziridine formation (67 or 68) and ring expansion, with the final stereochemistry depending on that introduced in the conjugate addition step. Using the auxiliary (4S,5R)1,5-dimethyl-4-phenylimidazolidin-2-one, the authors compared AlMe2Cl, BF3  Et2O, MgBr2  Et2O, Sc(OTf)3, and TiCl4 in the conjugate addition. The best results—9:1 dr and .95% yield of 65/66—were obtained with the use of BF3  Et2O. The authors had expected BF3 to give the opposite stereoselectivity, the reverse of that obtained with AlMe2Cl, MgBr2  Et2O, and Sc(OTf)3; they presumed that BF3, with only one coordination site, would not form a chelate with the two carbonyls as the other Lewis acids could. In a further investigation,13 Cardillo et al. performed 1H, 13C, and 11B NMR analysis of imides 70 (Scheme 5.12A) in the presence of BF3  Et2O. In the 1H NMR spectra for each imide, they identified signals for a complex present when either 1 equiv. or 2 equiv. of BF3  Et2O was used. Taking this to be the complex responsible for the observed

O

O N

N Me

then BnONH2 –78°C

R Ph 61 R = Alkyl, O

Bu2BOTf CH2Cl2

Me

Me

O N Bu2B O OTf

BnO

Me N re

NH

62

Ph

Me

+

R OPh

N Me

N R

si

BnONH2

O

O

BnO

NH

O

O N

N Me

R 63

Ph

Me

Scheme 5.10 Diastereoselective conjugate additions promoted by dibutylboron triflate (Bu2BOTf).11

151

Stereoselective Conjugate

O N

O N 64

Ph

NH2OBn Lewis aci d O N

O

NHOBn

N

N

O

67

69

R

R = Me, Ph

TEA

O

NHOBn N

N 66

Ph

O MeO

Ph

AlMe2Cl

O

H N

N

+ O

O N

65

Ph

N

O

O

H N

N Ph

68

Scheme 5.11 Oxazoline synthesis beginning with diastereoselective conjugate addition of O-benzylhydroxylamine.12

(A)

BF3 BF3 O N

O

O BF3·Et2O

R

N Ph

70a, R = Me 70b, R = i-Pr

N

O N

R BnONH2

Ph O

(B) Cβ-si face (hindered O due to LA)

N N

O

NHOBn

N Ph

N BnONH2

LA

O

Steric interaction between LA and Ph group

LA = BF3 or AlMe2Cl

Scheme 5.12 Models by Cardillo (A) and Duarte (B) for coordination of N-alkenoylimidazolidinones to Lewis acids.13,14

152

Imides

diastereoselectivity, the authors considered three possibilities: (1) chelation of one BF3 by both carbonyls, resulting in pentacoordinate boron; (2) chelation of one BF3 by both carbonyls, displacing F2 and forming BF42; and (3) coordination of the carbonyls to two different BF3 molecules, with the carbonyls in a parallel orientation due to electrostatic attraction. From the 11B NMR spectra of 70a-BF3  Et2O obtained at multiple temperatures and equivalents of BF3  Et2O, the authors concluded that the third possibility was the most likely, involving tetracoordinate boron without BF42 formation. Later, Duarte and coworkers14 challenged the coordination mode proposed by Cardillo et al. In their explanation, Duarte et al. applied their previously described alternative to Evans’ rationalization of stereoselectivities obtained in Lewis acid
catalyzed Diels
Alder reactions of alkenoyloxazolidinones. Their approach for analyzing Cardillo’s conjugate additions included NMR studies and computational methods. The NMR data agreed with Cardillo’s results and also demonstrated that complete complexation of the substrate (coordination of both carbonyls) occurred with 1.0 equiv. of Mg(ClO4)2 (previously shown to effectively chelate N-acyloxazolidinones) but required 2.0 equiv. of AlMe2Cl or BF3. At lower Lewis acid concentrations, the alkenoyl carbonyl was preferentially complexed first. Furthermore, NOESY experiments indicated that the carbonyl groups in the AlMe2Cl and BF3 complexes were antiparallel, and theoretical data agreed with the experimental results regarding the conformations and coordination modes of complexes. The computational results further demonstrated that chelated complexes of AlMe2Cl or BF3 would afford very low stereoselectivity and that parallel carbonyl bicomplexes, as proposed by Cardillo for BF3, would result in selectivity opposite that observed. Duarte’s findings supported a model with antiparallel carbonyls; the Lewis acid on the alkenoyl carbonyl, because of steric repulsion with the auxiliary’s phenyl substituent, would partially shield the Cβ-si face, favoring nucleophilic attack at the Cβ-re face and leading to the observed diastereoselectivity (Scheme 5.12B). 5.4.1.3 Use of Chiral Lewis Acid Catalysts In 1996 Falborg and Jørgensen reported chiral Lewis acid
catalyzed enantioselective conjugate additions of O-benzylhydroxylamine to N-alkenoyloxazolidinones 71 to provide 72 (Scheme 5.13).15 The authors first screened TiCl2-TADDOLate complexes, including 73 and TiCl2BINOLate complex 74, in the reaction of an oxazolidinone crotonate

153

Stereoselective Conjugate

R

Ph

O

O N

73 or 74 (10 mol%) O

+

Ph

O

NH2

O

N

H

R *

O

O N

71

72

R = Me, Pr, Ph

R = Me, Pr, Ph

O

Ph Ph Me Me

O O

O TiX2 O

O TiCl2 O

Ph Ph 73a X = Cl 73b X = OTf

74 (TiCl2-BINOL)

Scheme 5.13 Conjugate additions of O-benzylhydroxylamine catalyzed by chiral titanium-based Lewis acids.15

(71, R 5 Me) at 0°C and then studied reactions of propyl- and phenylsubstituted imides (71, R 5 Pr, Ph) promoted by 73 at room temperature. They also performed reactions at 220°C with each alkenoyloxazolidinone but found that temperature did not significantly affect enantiomeric excess. In the catalyst screening, catalysts 73a and 73b gave some of the best ee’s (29% and 28%, respectively), but the use of 73b resulted in greater conversion, which the authors attributed to greater Lewis acidity imparted to the catalyst by the presence of triflate ligands rather than chloride ligands. In the reactions of propyl- and phenyl-substituted substrates, the triflate catalyst gave 94% and 69% conversion and 35% and 42% ee, respectively. The chloride catalyst gave lower conversion with the phenyl substrate, similar to the result seen in the solvent screening. The authors determined the crotonate addition product’s β carbon configuration to be S, meaning that the conjugate addition predominantly occurred via si-face approach of O-benzylhydroxylamine. They proposed that the alkenoyloxazolidinone underwent bidentate coordination to the Lewis acid, forming a hexacoordinate titanium center in the active catalyst, but noted that the relatively low enantioselectivities did not allow them to identify which of five possible complexes (with different relative positions of ligands) might be involved. Chiral Lewis acid
catalyzed conjugate additions of O-benzylhydroxylamine with higher ee’s were reported by Sibi et al. in 2002.16 A notable feature of these reactions, catalyzed by a chiral bisoxazoline
MgBr2 complex, was that opposite product enantioselectivities resulted at different temperatures. Initially, conjugate addition to

154

Imides

crotonates 75 with various oxazolidinone and pyrrolidinone templates and chiral ligand 26 (Scheme 5.14) was investigated at 0°C and 260°C. The addition products 76 were obtained in 43%
71% ee with no significant improvement in enantioselectivity at lower temperature. Strikingly, however, the addition product of the 4,4-dimethyloxazolidinone crotonate (X 5 O, R1 5 Me, R2 5 Me) formed predominately with (R) configuration at 0°C but (S) configuration at 260°C. Repetition of the reaction at different temperatures showed that this reversal of selectivity occurred between 220°C and 240°C. The authors conducted additional experiments to determine the effects of the Lewis acid, the chiral ligand, the template structure, and the enoate’s β-substituent. The use of salts with more weakly coordinating counterions—Mg(ClO4)2, Mg(OTf)2, and MgI2—afforded no change in selectivity with temperature. Reactions catalyzed by ligands 77 gave low to moderate ee’s and no temperaturedependent selectivity change. Several oxazolidinone and pyrrolidinone templates with methyl and phenyl substituents at the 4-position all allowed for temperature-dependent selectivities and moderate to excellent yields, and different alkyl β-substituents provided similar, generally consistent results. To explain these results, Sibi et al. suggested that the selectivities might be due to a temperature-dependent change in the substrate
catalyst coordination complex. Assuming bidentate coordination of the substrate, they considered five- and six-coordinate complexes to be more likely than tetrahedral since the selectivity indicated by modeling the tetrahedral complex was opposite that actually obtained under conditions favoring low coordination number: high temperature, weakly coordinating counterion, and bulky ligand or substrate. The authors tentatively postulated O

O

O

O

NHOBn

MgBr2/ligand (30 mol%) X

N R1

R2 R1

O

75

X = O, CH2 R1 = H, CH3, Ph R2 = Alkyl

N

BnONH2, CH2Cl2 R1 O

O N

R1

76

O

N 26

R2

O N

R

N 77

R

R = t-Bu, Bn, Ph

Scheme 5.14 Conjugate addition of O-benzylhydroxylamine with temperaturedependent enantioselectivity.16

Stereoselective Conjugate

155

that the complex of a bulky 4,4-disubstituted oxazolidinone alkenoate with MgBr2 and bulky ligand 26 would be octahedral, with both bromides bound, at low temperatures but would be five-coordinate, with only one of the bromides bound, at higher temperatures, effecting different face selectivities in the conjugate addition. Previously, Sibi et al. had developed enantioselective conjugate additions of O-benzylhydroxylamine to N-alkenoyl-3,5-dimethylpyrazoles 78 catalyzed by complexes of MgBr2 and ligand 26, obtaining moderate to good yields and up to 97% ee in MgBr2-catalyzed reactions.17 To determine whether these reactions were reversible under the conditions employed, the authors subjected the racemic conjugate addition product from N-crotonoyl-3,5-dimethylpyrazole to the reaction conditions in the presence of oxazolidinone crotonate 79 (Scheme 5.15). Only the starting materials—no crossover product formed by conjugate addition of O-benzylhydroxylamine to the oxazolidinone—were recovered, indicating that the conditions did not allow for any significant reversibility. As a control experiment, the oxazolidinone crotonate alone was subjected to the same conditions in the presence of O-benzylhydroxylamine; after 22 h, the conjugate addition product 80 was obtained in 82% yield and 28% ee (Scheme 5.15), similar to the results obtained by Falborg and Jørgensen using TiX2-TADDOLate catalysts (Scheme 5.13). In 2006 Kikuchi and coworkers investigated rare-earth (RE) metal complexes with chiral pybox-based ligands 84 and 85 as catalysts for the conjugate addition of O-benzylhydroxylamine to N-alkenoyloxazolidinones (Scheme 5.16).18 The authors screened different RE metals, substituents on the pybox ligand, and structures of the alkenoyloxazolidinone substrate. Reactions of an oxazolidinone crotonate (81, R1 5 Me, R2 5 H) using an i-Pr-pybox ligand (84, R 5 i-Pr) and various RE O N

N

NHOBn CH3

O + O

78

O N

MgBr2/26 (1 equiv.) CH3

CH2Cl2, –60°C, 3 h

O

X

O

O N

79 O O

N

CH3 79

CH3 80

BnONH2 MgBr2/26 (1 equiv.)

O

NHOBn

CH2Cl2, –60°C, 22 h

O O

O N

NHOBn * CH3

80

Scheme 5.15 Crossover experiment and control reaction to assess reversibility of conjugate addition.17

156

Imides

R1

N 81

BnONH2 RE(OTf)3/ligand (5 mol%)

O

O

O

MS 4 Å, CH2Cl2, 0°C

BnO

NH

R1

R2

N 82

R2 R1 = Alkyl R2 = H, Me O

84

R

O

+

NH

O

R1

N H

OBn

83

R2

O

N N

N

N

N R

O

O

N

R2

BnO

O

O

85

R = i-Pr, t-Bu, Ph, Bn, CH2OH

Scheme 5.16 Chiral RE complex
catalyzed enantioselective conjugate additions of O-benzylhydroxylamine.18

triflates gave excellent conversions and varying ratios of products 82 and 83, and the use of Sc(OTf)3 provided the highest enantioselectivity. The enantioselectivity of the reaction with Sc(OTf)3 was significantly lower at 220°C and 250°C and slightly lower at room temperature. When compared with other pybox ligands in the same reaction, the i-Pr-pybox ligand afforded the highest enantioselectivity. Finally, substrates with various β-alkyl substituents, in reactions using Sc(OTf)3 and the i-Pr-pybox ligand at 0°C, formed the corresponding products in good conversions (80% to .99%) and enantioselectivities (80%
91% ee of 82). Larger β-alkyl groups were correlated with higher 82/83 product ratios. Finally, the reaction of a 4,4-dimethyl-substituted oxazolidinone crotonate (R1 5 R2 5 Me) yielded only the corresponding conjugate addition product—no amidation side product—in 91% conversion and 80% ee. Didier et al. in 2011 studied samarium iodobinaphtholate 89 as an alternative catalyst for the conjugate addition of O-benzylhydroxylamine to N-alkenoyloxazolidinones 86 (Scheme 5.17),19 having previously reported its use for the same reaction with anilines as nucleophiles. In preliminary experiments, samarium diiodide gave better conversions than did other achiral catalysts. Samarium iodobinaphtholate
catalyzed reactions of an oxazolidinone crotonate (R1 5 Me, R2 5 H) gave the conjugate addition product exclusively at lower temperatures and afforded the maximum enantiomeric excess at 240°C, with lower ee’s below this point. The authors attributed the nonlinear variation in enantioselectivity to equilibria among various monomeric and dimeric catalytic species. In an examination of substrate scope, β-alkyl and β-ester substrates were converted to the corresponding conjugate addition products in generally good yields

157

Stereoselective Conjugate

O

O N

R1 86

BnO

BnONH2 catalyst (10 mol%)

R1

O CH2Cl2, –40°C

R2

NH

R1 = H, alkyl, CO2Et, Ph R2 = H, Me

N

87

BnO

O

O

+

O

NH

O

R1

R2

88

R2

N H

OBn

O Sm I · (THF)2 O 89

Scheme 5.17 Samarium iodobinaphtholate
catalyzed conjugate additions of Obenzylhydroxylamine.19

(76%
84%) and enantioselectivities (83%
88% ee) with lower yield (59%) and enantioselectivity (52% ee) from a β-isopropyl substrate. The reactions of β-phenyl and α-methyl substrates, conducted at room temperature, gave poor results: the β-phenyl substrate afforded the corresponding conjugate addition product 87 in moderate yield and low enantioselectivity, and only addition/amidation product 88 formed in the reaction of the α-methyl substrate.

5.5 CONJUGATE ADDITION TO α-SUBSTITUTED ACRYLIMIDES In 2001 Pratt et al. (from British Biotech Pharmaceuticals) reported the conjugate addition of O-benzylhydroxylamine to α-substituted acrylimide 90 (Scheme 5.18).20 They noted that they chose the dimethyl-substituted (S)-4-benzyl-2-oxazolidinone auxiliary for its lesser tendency to undergo ring opening compared with an (S)-4-benzyl-2-oxazolidinone lacking the methyl groups. The product 91 was formed with .90% diastereomeric excess and was isolated as a single diastereomer as its tosylate salt. Further reactions converted the product to BB-3497, a peptide deformylase (PDF) inhibitor with antibacterial activity in vivo. Bn

Bn BnONH2, rt

N O

O O

90

70%

BnO

H2 N

N O

TsO

O O

91

OH N

O

H N

O N

O

H BB-3497

Scheme 5.18 Diastereoselective conjugate addition of O-benzylhydroxylamine in the synthesis of BB-3497.20

158

Imides

In 2008 Liu and coworkers (Novartis) published their methods for the scale-up synthesis of LCD320, another PDF inhibitor (Scheme 5.19).21 Conjugate addition of O-benzylhydroxylamine to intermediate 92, using (S)-4-benzyl-2-oxazolidinone as the chiral auxiliary, featured as a key step in their route. The reaction gave B3
4:1 dr, but the product 93 was isolated in 60%
64% yield as its tosylate salt containing ,1% of the minor diastereomer. Upon scale-up in a pilot plant, much lower diastereoselectivity (3:1 to 2:3) resulted, and significant amounts of amidation product 94 formed. The authors determined that residual Li1 from the previous step (installment of the chiral auxiliary) was responsible for the poorer results; to solve this problem, they implemented three aqueous washes instead of one in the purification of 92, reducing the Li1 content to 1 ppm. Several other groups—Pichota et al.22 in 2008, Shi et al.23 in 2010, and Yang et al.24 in 2014—have also used the (S)-4-benzyl-2oxazolidinone auxiliary containing substrate 95, 98, and 101 for conjugate additions of O-benzylhydroxylamine and O-(p-methoxybenzyl)hydroxylamine to provide products 96, 99, and 102. The conjugate addition products were converted to structurally diverse PDF inhibitors 97, 100, and 103. Scheme 5.20 highlights these reactions and the target compounds with potential antibacterial properties. In 2008 Vögtle and coworkers (Novartis) reported scalable routes to perfluoroalkane-tagged 5,5-diphenyl-2-oxazolidinone (DIOZ) auxiliaries 104
106, enabling purification by fluorous solid-phase extraction, and demonstrated their use for the diastereoselective conjugate addition of O-benzylhydroxylamine in the synthesis of β2-N-Fmoc-phenylalanine 109 (Scheme 5.21).25 The authors prepared all three auxiliaries but chose

O

O N

O

2) TsOH·H2O ethyl acetate, rt Ph

O

O

1) BnONH2·HCl NaHCO3, toluene, rt

N

CHO N

O O N H

Ph

60%

F

93 +

HO

N

H2N TsO OBn

92

O

N N

LCD320

O N H

O

Ph

94

Scheme 5.19 Diastereoselective conjugate addition of O-benzylhydroxylamine in the synthesis of LCD320.21

159

Stereoselective Conjugate

Pichota et al.: O

1) BnONH2 (neat) 2) TsOH, ethyl acetate

O

R N 95

O OBn R HN

3) Na2CO3

O

96

Ph

O

OH N

O

O

O Ph

O

O

O

1) O-(p-methoxybenzyl)hydroxylamine 50°C, 24 h

O N

2) TsOH, Na2CO3, ethyl acetate/H2O Ph

58%

98

Y

O

MeO

N O

Ph

99

HO

O

Bu

N

N O

100

R1 N R2

O

NR1R2 = Various heterocyclic, carbocyclic, and aniline-based groups attached through N

Yang et al.: O

O

Bu

H N

H

1) O-(p-methoxybenzyl)hydroxylamine 45°C, 24 h 2) TsOH, ethyl acetate

O N

101

N

97 Y = NH or O R = Bu, Pr, pentyl, cyclopentylmethyl, or Bn

Bu

O

N

N

Shi et al.:

R3

R

Ph

3) aq. Na2CO3, ethyl acetate 60%

R3 O

MeO

O

H N

O N

O

102

Ph

R3 = n-Pr or cyclopentyl H HO

X=

O N

or

O N

O N

R3 X

N R5

R4

103 O NR4R5 = Various heterocyclic, carbocyclic, and aniline-based groups attached through N

Scheme 5.20 Conjugate additions of O-benzylhydroxylamine in the syntheses of other PDF inhibitors.22
24

106 for the synthesis since 106 was easiest to prepare yet displayed chromatographic properties similar to those of the other two auxiliaries. They synthesized both enantiomers of β2-N-Fmoc-phenylalanine by using opposite enantiomers of the chiral auxiliary. In each case, the diastereomeric conjugate addition products formed from addition to 107 to

160

Imides

O O

O

O N

BnONH2

R2

O

O N

R2

NH O

THF, 72°C, 24 h 70% 108

107 R2

R2

O

O O

O

NH

O NH

HO

R2

R1O

NH O

R 1O

R2

104 R1 = Si(CH(CH3)2)2CH2CH2C8F17 105 R1 = CH2(CF2)7CF2H

106 R2 = C2H4C6F13

O 109

Scheme 5.21 Use of perfluoroalkane-tagged chiral auxiliaries for the synthesis of β2N-Fmoc-phenylalanine.25

provide 108 as an B8.3:1 mixture, and the diastereomeric excess increased to 93% upon formation and recrystallization of the corresponding tosylate salt. The overall syntheses afforded each enantiomer of β2-NFmoc-phenylalanine with .95% ee.

5.6 N-SUBSTITUTED HYDROXYLAMINES Asymmetric conjugate addition of N-substituted hydroxylamines 111 to enoates 110 or 116 constitutes a route to chiral isoxazolidinones 115 and β-amino acids via intermediates 112
114 and 117. Compared with O-alkylhydroxylamines and simple alkylamines, N-alkylhydroxylamines react more rapidly in conjugate addition to alkenoates 110; to explain this reactivity difference, Niu and Zhao proposed a concerted mechanism in which the hydroxylamine adds to the double bond via a five-membered cyclic transition state (Scheme 5.22).26 In support of the proposed mechanism, deuterated N-methylhydroxylamine added to ethyl cinnamate with high diastereoselectivity to give product 118 with a cis relationship between the protons of the isoxazolidinone ring. Likewise, the reaction of α-deuterated esters 119 and 121 with N-methylhydroxylamine yielded the corresponding syn addition products. The authors also showed that the conjugate addition could be applied with various α,β-disubstituted alkenoates and N-alkylhydroxylamines to diastereoselectively provide the

161

Stereoselective Conjugate

H H

CO2Et + H N

R1

R2

110

O

CO2Et

R1 R2 H N H δ+ O δ−

H

111

H

CO2Et

R1 H N O

R2

112 O

Ph

MeNDOD•DCl

116

Ph H

OEt OD

ZnCl2 84%

117

R

OEt

(a) MeNHOH•HCl, R Et3N, THF H

O

O

O

119 R = Ph,

120

Ph H

O

O N O

OEt (a) MeNHOH•HCl, O Et3N, THF D

(b) ZnCl2

D

O 115

118

O

N O

N

D H O

N

R2

R1

114

D H

H D O

CO2Et R2 N H OH

113

Et3N, THF OEt

H

H R1

(b) ZnCl2

121

OD H O

H N O 122

O O

Scheme 5.22 Concerted alkenoates.26

mechanism

of

N-alkylhydroxylamine

addition

to

corresponding isoxazolidinones, affording control over the relative stereochemistry at the α and β carbons. As reported in a 1998 paper, Ishikawa et al. pioneered the use of chiral Lewis acid complexes to effect enantioselective conjugate additions of N-benzylhydroxylamine to enoates bearing achiral oxazolidinone auxiliaries leading to isoxazolidinones 124 or 127 (Scheme 5.23).27 They termed the Lewis acid
N-benzylhydroxylamine complex a “Lewis acidhydroxylamine hybrid reagent (LHHR)” and proposed the strategy shown in Scheme 5.23 for the reaction of generalized enoate 123. In their experiments, reactions of an oxazolidinone crotonate (125 or 126, R1 5 Me) using metala-1,3-dioxolane-type catalysts 128 gave, at best, moderate yield and low enantioselectivity of the (R) product, but those using metala-1,3-dioxepane-type catalysts 129 gave better results. With the same substrate, catalysts 129a and 129b each provided good yield and 63% ee. Reactions of benzyl-substituted (E)- and (Z)-enoates using catalyst 129a proceeded with low to moderate yields and 71% and 43% ee, respectively, while the reaction of a β-phenyl substrate yielded only a trace of the corresponding conjugate addition product. Sibi and Liu noted the lower reactivity of β-aryl enoates in chiral Lewis acid
catalyzed conjugate additions of nitrogen nucleophiles and conducted studies identifying factors that could enhance reactivity (Scheme 5.24).28 Employing chiral ligand 26 with MgBr2 as the Lewis

162

Imides

L

L O M L N H O

Bn O R1

LHHR

R1

X

Bn

N

M O

R1

X

L R1

O X

O N O

Bn

123

124 O

O N

R1

R1 O

or

N

125 R1 = Me, Bn, Ph

Z

O M ONHBn O

Z

O

126 R1 = Bn

O LHHR (1 equiv.) R1 * N O THF Bn 0-22°C, 23°C, or rt 127 R1 = Me, Bn, Ph R

Me Me TBSO O Al ONHBn O TBSO Me Me

Ph Ph O O M ONHBn O O Ph Ph

R2 Me

128 Z = CO2i-Pr, Ph, CONMe2 M = Al, B

O

O

129a M = Al, R2 = Ph 129b M = Al, R2 = Me 129c M = B, R2 = Ph

O Al ONHBn O R 129e R = H 129f R = SiPh3

129d

Scheme 5.23 Chiral Lewis acid
catalyzed enantioselective conjugate additions of N-benzylhydroxylamine.27

Lewis acid/ligand 26 (30 mol%) O R2NHOH (1.1 or 2.2 equiv.)

O Z

R1

CH2Cl2, –60°C

130 R1 = Me, aryl, heteroaryl Me

N

Z=

O

N

R2 O

R1 131 R1 = Me, aryl, heteroaryl

O

O N

N 26

O

N O

O N

N

N

Lewis acid = MgBr2, MgI2, or Mg(ClO4)2 R2 = PhCH2, (Ph)2CH, or 4-MeOC6H4CH2

Me A

B

C

D

Scheme 5.24 Enantioselective conjugate additions of N-benzylhydroxylamine to β-aryl-substituted enoates.28

acid at 260°C, they studied the conjugate addition of N-benzylhydroxylamine to crotonates (130, R1 5 Me) with several different achiral templates. The reaction of the 3,5-dimethylpyrazole crotonate allowed for a direct comparison with Sibi et al.’s previous work involving conjugate addition of O-benzylhydroxylamine to this substrate: N-benzylhydroxylamine reacted significantly faster than O-benzylhydroxylamine under the same conditions. Pyrrolidinone template C imparted comparatively high reactivity, afforded good yield and enantioselectivity of the conjugate

163

Stereoselective Conjugate

addition product, and subsequently served as the template for further experiments. In the same reaction, the alternative nucleophiles N-benzhydrylhydroxylamine and N-(p-methoxybenzyl)hydroxylamine formed the corresponding adducts 131 with similar ee but reacted more slowly than N-benzylhydroxylamine. Finally, the conjugate addition of N-benzylhydroxylamine was performed with β-aryl- and β-heteroaryl-substituted enoates as substrates and MgI2 and Mg(ClO4)2 (which promoted faster reactions than did MgBr2) as Lewis acids; overall, 53%
87% isolated yields and 60%
96% ee’s were obtained. Experiments using BnNDOD as the nucleophile as in Niu and Zhao’s study26 suggested that conjugate addition under these conditions occurred via a concerted mechanism. In 2001 Sibi and Liu again reported methodology for chiral Lewis acid
catalyzed conjugate additions to enoates, this time using pyrazolidinone-based templates bearing chiral relay groups (denoted by Z) for the addition of N-(p-methoxybenzyl)hydroxylamine (Scheme 5.25).29 Templates with diphenylmethyl and 1-naphthylmethyl relay groups, intended to amplify the chirality introduced by the chiral Lewis acid, afforded significantly greater ee’s at higher temperatures in reactions of crotonates (R2 5 Me) when compared with a nonrelay (unsubstituted pyrrolidinone) template. To develop this methodology for the conjugate addition reaction, the authors first evaluated chiral bisoxazoline ligands with Mg(ClO4)2 and Zn(OTf)2 as catalysts for the reaction of a crotonate with a benzyl relay group (132, R1 5 Me, Z 5 Bn, R2 5 Me) at 0°C. Although poor to moderate enantioselectivities for 133 resulted in most cases, the reaction catalyzed by the Zn(OTf)2/134 combination gave 70%

O

N H

O

OH

MeO R1

N N R1 Z

R2

O

Lewis acid/ligand (30 mol%) CH2Cl2, 0°C

132 R1 = Me, H Z = H, Et, Bn, 2-CH2-naphthyl, 1-CH2-naphthyl, CH(Ph)2 R2 = Me, Ph

O

N OMe

* R 2

133 R2 = Me, Ph

O

O N

N 134

O

O N

N 26

Scheme 5.25 Enantioselective conjugate additions using chiral relay templates.29

164

Imides

ee. The authors next screened different relay substituents in the reaction of crotonates at 0°C with Lewis acid/ligand combinations Zn(OTf)2/134 and Mg(ClO4)2/26. Strikingly, the reactions catalyzed by the magnesium and zinc complexes gave opposite selectivities, yielding the (R) and (S) enantiomers, respectively. The best overall yields (77% and 75%) and enantioselectivities (81% and 75% ee) resulted with the 1-naphthylmethyl relay group; the reaction with the diphenylmethyl relay group led to relatively high enantioselectivity (84% ee) with Mg(ClO4)2/26 but only moderate enantioselectivity (57% ee) with Zn(OTf)2/134. With these two relay groups, the reaction gave good enantioselectivities even at room temperature when Mg(ClO4)2/26 was used. With the 1-naphthylmethyl relay group at 225°C, the magnesium and zinc complexes afforded 96% ee of the (R) product and 83% ee of the (S) product, respectively. Finally, cinnamates (R2 5 Ph) with different relay groups underwent the conjugate addition catalyzed by Mg(ClO4)2/26 in good yields at 0°C, and a cinnamate with the diphenylmethyl relay group formed the corresponding (S) product in 88% ee. Although methods initially had been developed for enantioselective conjugate additions of N-substituted hydroxylamines to acrylimides with one β-substituent, Sibi and coworkers expanded the reaction scope to α,β-disubstituted acrylimides 135, enabling enantioselective syntheses of α,β-disubstituted-β-amino acids 137 (Scheme 5.26).30 The concerted mechanism of N-benzylhydroxylamine addition would facilitate

R4

BnNHOH MgX2/26 (5 or 30 mol%)

O

O N R3

O

O

N

Bn

R2

135 R1 = Alkyl, Ph R2 = Me, Et, Br, Ph R3 = H R4 = i-Pr

CH2Cl2, 25ºC or –40°C O

O

R2

O

H2, Pd/C

R1

HO

Dioxane 60°C

R1

NH2 R1

R2 137

136

N

N

X

26

X O

N

O

R4 NH

Mg O

R2

N R1

O

138

Scheme 5.26 Enantioselective conjugate additions of N-benzylhydroxylamine to α,β-disubstituted acrylimides.30

Stereoselective Conjugate

165

simultaneous control over both of the resulting stereocenters, but control over s-cis and s-trans enoate rotamers would be essential for high enantioselectivity as well as diastereoselectivity. The authors employed secondary imide (R3 5 H) templates, hypothesizing that such a template would provide rotamer control while also maximizing reactivity: steric interaction between the enoyl α-substituent and a larger R3 substituent would promote out-of-plane twisting that would break conjugation and decrease β-carbon electrophilicity. Using chiral ligand 26 (30 mol%), various achiral templates, and several magnesium-based Lewis acids (30 mol%), the authors systematically optimized the conjugate additions of N-benzylhydroxylamine to tiglates (R1 5 R2 5 Me). Poor yields of 136 resulted from the use of pyrrolidinone, oxazolidinone, and N-methyl templates; among secondary imide templates, R4 5 i-Pr led to good yield and the highest stereoselectivity (96% de, 96% ee) when used with Mg(NTf2)2 as the Lewis acid at 240°C. The optimized conditions with 5 mol% catalyst were then applied to evaluate the reaction with variously substituted substrates. In most cases, the reaction gave good to excellent yields, excellent diastereoselectivities, and good to excellent enantioselectivities; poor to moderate yields were obtained from substrates with isopropyl and phenyl β-substituents and moderate enantioselectivity (60% ee) from an α,β-diethyl-substituted substrate. Hydrogenolysis of selected products yielded the corresponding β-amino acids, and on the basis of the product stereochemistry, the authors proposed cis octahedral model 138.

5.7 CONCLUSION Stereoselective conjugate additions of N
N and N
O nucleophiles to α,β-unsaturated imides, together with subsequent transformations, have enabled the construction of diverse structures, including pyrazolidinones from alkylhydrazines as nucleophiles; nitrones, oxime ethers, and β-hydroxy carboxylic acid derivatives from oximes; chiral aziridines, oxazolines, and β-amino acids from O-substituted hydroxylamines; and isoxazolidinones and β-amino acids from N-substituted hydroxylamines. Most of these reactions have involved conjugate addition to acrylimides with only one α or β substituent and have achieved control over the configuration at the single new stereocenter, but the concerted mechanism of N-alkylhydroxylamine addition, together with chiral Lewis acid catalysis, has allowed for configurational control of the two new stereocenters resulting from addition to α,β-disubstituted acrylimides. A variety of chiral

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ligands, most notably bisoxazolines, have been used with various Lewis acids to promote stereoselective reactions of achiral substrates. Auxiliaries have included chiral and achiral oxazolidinones, pyrrolidinones, imidazolidinones, acyclic imides, and pyrazolidinones; the use of achiral pyrazolidinones with chiral relay substituents effectively amplified the chirality imposed by a chiral Lewis acid
bisoxazoline complex for N-(p-methoxybenzyl)hydroxylamine addition. Together, the methods and applications reviewed in this chapter demonstrate the broad scope and potential utility of these reactions for the synthesis of structurally diverse and potentially bioactive compounds.

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